Desquamation/epidermal renewal of the skin and/or combating skin aging

ABSTRACT

Cinnamic acid and derivatives thereof are well suited for promoting desquamation and/or stimulating epidermal renewal and/or combating intrinsic/extrinsic aging of the skin of a human subject in need of such treatment, by topically applying thereto, for such period of time as required to elicit the desired response, a cosmetically/therapeutically effective amount of cinnamic acid and/or of at least one derivative thereof.

CROSS-REFERENCE TO RELATED AND PRIORITY APPLICATIONS

This application is a continuation of U.S. application Ser. No.09/305,213, filed May 5, 1999, now U.S. Pat. No. 6,562,353, incorporatedby reference herein in its entirety and relied upon, which claimspriority under 35 U.S.C. § 119 of FR-98/05967, filed May 12, 1998,expressly incorporated by reference therein.

BACKGROUND OF THE INVENTION

1. Technical Field of the Invention

The present invention relates to promoting desquamation of the skinand/or stimulating epidermal renewal and/or combating aging of the skinby topical application thereto of cinnamic acid or derivative thereof,or composition comprising same.

The compounds/compositions of this invention are especially well suitedfor promoting desquamation of the skin and/or stimulating epidermalrenewal and/or combating intrinsic and/or extrinsic aging of the skin,as well as for nontherapeutically treating the skin to promotedesquamation and/or combat aging of the skin.

2. Description of the Prior Art

Desquamation is a natural phenomenon associated with the fact that theepidermis, which constitutes the upper layer of the skin, is in constantregeneration. The epidermis consists of several layers of cells, thedeepest of which is the basal layer consisting of undifferentiatedcells. These cells differentiate and migrate towards the surface of theepidermis over time, constituting the various layers thereof, until theyform at the surface of the epidermis the corneocytes, which are deadcells, which are removed by desquamation. This loss of surface iscompensated for by the migration of cells from the basal layer towardsthe surface of the epidermis. This entails perpetual renewal of theskin. Forced removal of the horny layer accelerates the renewal andmakes it possible to combat aging.

At the same time, these cells continue their differentiation, the finalstage of which is the corneocyte. These are dead cells which make up thefinal layer of the epidermis, namely, the outermost layer also known asthe stratum corneum.

Aging of the skin resulting from the effects of intrinsic or extrinsicfactors on the skin is reflected by the appearance of wrinkles and finelines, by yellowing of the skin which develops a parchment-likeappearance accompanied by the appearance of pigmentation blemishes, bythe disorganization of the elastin and collagen fibers, causing a lossof elasticity, flexibility and firmness, and by the appearance oftelangiectases.

Certain of these signs of aging are more particularly associated withintrinsic or physiological aging, namely, with “normal” aging due to ageor chronobiological aging, whereas others are more specific to extrinsicaging, namely, aging caused in general by the environment; this relatesmore particularly to photoaging due to exposure to sunlight, to light orto any other radiation, whether natural or artificial.

The present invention relates to not only intrinsic or physiologicalaging, but also to extrinsic aging.

The changes in the skin due to intrinsic aging are the consequence of agenetically programmed senescence involving endogenous factors. Thisintrinsic aging causes, in particular, a slowing down or retarding ofthe renewal of the skin cells, which is reflected essentially by theappearance of clinical impairments such as reduction in the subcutaneousadipose tissue and the appearance of small wrinkles or fine lines, andby histopathological changes such as an increase in the number andthickness of elastic fibers, a loss of vertical fibers from the membraneof the elastic tissue, and the presence of large irregular fibroblastsin the cells of this elastic tissue.

By contrast, extrinsic aging causes clinical impairments such as largewrinkles and the formation of a flaccid and weathered skin, andhistopathological changes such as excessive accumulation of elasticmaterial in the epidermis and degeneration of the collagen fibers.

Various active agents suggested for combating aging of the skin areknown in the prior art.

Thus, U.S. Pat. No. 4,603,146 describes the use of retinoic acid andderivatives thereof in cosmetic compositions for combating skin aging.

Moreover, many patents and publications (see, for example, EP-A-413,528)describe, and numerous commercially available commercial cosmeticcompositions include, α-hydroxy acids, such as lactic acid, glycolicacid or citric acid, for treating aging of the skin.

Too, the β-hydroxy acids, and more especially salicylic acid andderivatives thereof, are known for their desquamating properties (seeWO-A-93/10756 and U.S. Pat. No. 4,767,750).

All of the aforesaid prior art compounds elicit action against aging ofthe skin by promoting desquamation, i.e., the removal of the “dead”cells located at the surface of the horny layer of the epidermis. This“desquamating” property is also referred to, often incorrectly, as akeratolytic property.

However, the compounds of the prior art also present objectionable sideeffects, such as stinging, tautness and sensations of overheating andredness which are unpleasant for the user.

Need therefore continues to exist for antiaging agents having an actionwhich is at least as effective as that of the compounds of the priorart, but which do not present the disadvantages thereof.

SUMMARY OF THE INVENTION

Accordingly, a major object of the present invention is the provision ofactive agents for promoting desquamation of the skin and/or forstimulating epidermal renewal, while at the same time avoiding thestinging, tautness or sensations of overheating or redness which areunpleasant for the user and which to date have characterized the stateof this art.

Briefly, it has now surprisingly and unexpectedly been determined thattopically applying an effective amount of cinnamic acid or of at leastone derivative thereof onto the skin promotes the desquamation thereofand/or stimulates epidermal renewal and therefore combats skin aging.

Thus, this invention features formulating an effective amount ofcinnamic acid or at least one derivative thereof intocosmetic/therapeutic compositions that promote desquamation of the skinand/or stimulate epidermal renewal and/or combat intrinsic and/orextrinsic aging of the skin.

The present invention also features a non-therapeutic regime/regimen fortreating the skin to promote desquamation thereof and/or to stimulateepidermal renewal and/or to combat intrinsic and/or extrinsic aging ofthe skin.

DETAILED DESCRIPTION OF BEST MODE AND SPECIFIC/PREFERRED EMBODIMENTS OFTHE INVENTION

More particularly according to the present invention, it will beappreciated that cinnamic acid is present in trans-form in the essentialoils of basil and of cinnamon, in Peruvian balsamine and in cacaoleaves. The cis-form is present in the oil from Alpinia malacensis.

In the prior art, cinnamic acid or derivatives thereof have beenformulated into compositions for preventing bedsores (JP-07,242,558), asanti-ultraviolet active agents (U.S. Pat. No. 5,093,109), inpermanent-waving compositions (DE-3,301,515, DE-2,912,427 andEP-22,996), in hair lotions (JP-7,053,401 and JP-3,041,413), indepigmenting compositions (JP-5,221,845 and JP-1,186,811) and asantioxidants (EP-664,290).

However, to date the use of cinnamic acid or derivative thereof forpromoting desquamation of the skin and/or stimulating epidermal renewaland/or combating intrinsic and/or extrinsic aging of the skin wasunknown.

The present invention therefore features the use of an effective amountof cinnamic acid or of at least one derivative thereof, or compositioncomprised thereof, to promote desquamation of the skin and/or tostimulate epidermal renewal and/or to combat intrinsic and/or extrinsicaging of the skin.

The cinnamic acid or derivative thereof can be of natural or syntheticorigin. By the term “natural origin” is intended cinnamic acid orderivative thereof prepared from plant material in which they exist inthe natural state. By the term “synthetic origin” is intended cinnamicacid or derivative thereof, prepared via chemical synthesis orbiotechnology.

Thus, the term “cinnamic acid” connotes cinnamic acid or derivativethereof, of natural or synthetic origin, in purified form, or in anypreparation comprising same.

Exemplary cinnamic acid derivatives according to the invention, include,for example, mono- and polyhydroxycinnamic acids, alcohols, aldehydes,esters and derivatives thereof.

Cinnamic acid is the preferred compound according to the invention.

Too, the cinnamic acid or derivative thereof can be used either alone orin any admixture of same.

The amount of cinnamic acid or derivative thereof which can be usedaccording to the invention obviously depends on the desired effect andshould be an amount which is effective for promoting desquamation of theskin and/or stimulating epidermal renewal and/or combating intrinsicand/or extrinsic aging of the skin.

For example, the amount of cinnamic acid or of at least one derivativethereof according to the invention advantageously ranges, for example,from 10⁻⁶% to 10% and preferably from 10⁻³% to 5% of the total weight ofthe composition.

This invention also features compositions for promoting desquamation ofthe skin and/or stimulating epidermal renewal and/or combating intrinsicand/or extrinsic aging of the skin, comprising an effective amount of atleast cinnamic acid or at least one derivative thereof, formulated intoappropriate cosmetically/dermatologically acceptable medium therefor(diluent, vehicle or carrier).

In the compositions of the invention, the cinnamic acid or at least onederivative thereof can be present in an amount ranging from 10⁻⁶% to 10%and preferably from 10⁻³% to 5% of the total weight of the composition.

This invention also features a nontherapeutic regime/regimen forpromoting desquamation of the skin and/or stimulating epidermal renewaland/or combating intrinsic and/or extrinsic aging of the skin,comprising topically applying a cosmetic composition containing aneffective amount of cinnamic acid or derivative thereof onto the skin.

The subject compositions can be formulated into any known pharmaceuticalform such as, for example, as an emulsion, in particular an oil-in-wateror water-in-oil emulsion, or even in the form of a multiple emulsion.

They may also be provided in the form of an aqueous solution, which maybe gelled, or in the form of a lotion, for example a two-phase lotion,an ointment, a cream, a milk or a mousse (foam).

The compositions according to this invention may comprise an oily phasebased on animal, plant, mineral, silicone, fluoro and/or synthetic oil.

The oily phase may also comprise fatty alcohols or fatty acids, as wellas surfactants.

Exemplary are the hydrocarbon-based oils such as liquid paraffin orliquid petroleum jelly; perhydrosqualene; arara oil, sweet almond oil,beauty-leaf oil, palm oil, castor oil, avocado oil, jojoba oil, oliveoil or cereal germ oil; alcohols such as oleyl alcohol, linoleylalcohol, linolenyl alcohol, isostearyl alcohol or octyldodecanol. Alsoexemplary are the silicone oils such as PDMSs, optionally phenylated,such as phenyltrimethicones.

The oily phase may also comprise a makeup-removing oil such as a fattyacid ester, in particular the esters obtained from a straight- orbranched-chain alcohol having from 1 to 17 carbon atoms and from astraight- or branched-chain fatty acid having from 3 to 18 carbon atoms.

Representative such esters include dioctyl adipate, 2-ethylhexylpalmitate, diisopropyl adipate, 2-ethylhexyl hexanoate, ethyl laurate,methyl myristate, octyldodecyl octanoate, isodecyl neopentanoate, ethylmyristate, myristyl propionate, 2-ethylhexyl 2-ethylhexanoate,2-ethylhexyl octanoate, 2-ethylhexyl caprate/caprylate, methylpalmitate, butyl myristate, isobutyl myristate, ethyl palmitate,isohexyl laurate, hexyl laurate and isopropyl isostearate.

The oily phase advantageously constitutes from 5%-95% by weight in thecase of an emulsion.

The compositions according to the invention may also comprise, inaddition:

(i) an agent permitting the fatty phase to be placed in suspension, forexample a copolymer of C₁₀-C₃₀ alkyl acrylates and of acrylic ormethacrylic acid or ester thereof(Pemulen TR1, Pemulen TR2 and Carbopol1342 marketed by Goodrich); or an acrylamide/methylpropanesulfonic acidcopolymer (Sepigel marketed by SEPPIC), and/or

(ii) an agent for dispersing the fatty phase, such as an emulsifying orvesicular system based on vesicles, optionally of nanometric size,comprising ionic lipids (liposomes) or nonionic lipids, and inparticular the emulsifying systems which are well known to the art, andcomprising glyceryl stearate/PEG 100 stearate (CTFA), cetyl alcohol andstearyl alcohol.

The compositions of the invention too may comprise an agent formodifying its viscosity, and for providing more or less gelled textures,such as:

(iii) cellulose derivatives (carboxymethylcellulose,hydroxyethylcellulose or hydroxypropylmethylcellulose),

(iv) natural gums such as xanthan gum, guar gum or carob gum,scleroglucans, chitin or chitosan derivatives, and carrageenans,

(v) polycarboxyvinyl derivatives such as Carbomer (marketed by Goodrichunder the trademarks Carbopol 940, 951 and 980, or by 3V-Sigma under thetrademark Synthalen K or Synthalen L).

The compositions according to the invention may also compriseconventional additives and adjuvants for cosmetic/dermatologicalapplications, such as preservatives, antioxidants, fragrances, fillerssuch as kaolin or starch, or even hollow microspheres, pigments, UVscreening agents, sequestering agents, essential oils, dyestuffs,colorants, odor absorbers, hydrophilic or lipophilic active agents suchas moisturizers, in particular glycerol or butylene glycol,anti-inflammatory agents such as allantoin and bisabolol,anti-free-radical agents such as alantoin or bisabolol,anti-free-radical agents such as vitamin E or derivative thereof,soothing agents such as cornflower water or extract of iris,depigmenting agents, biological active agents such as urea, amino acids,vitamins and derivative thereof, proteins, salicylic acid andderivatives thereof, α-hydroxy acids, pyrrolidonecarboxylic acid and itssalts, and ceramides.

One skilled in this art will of course take care to select this or theseoptional complementary compounds, and/or the amount thereof, such thatthe advantageous properties of the compositions according to theinvention are not, or are not substantially, adversely affected by theaddition envisaged.

The subject compositions preferably have a pH which does not damage theskin, generally ranging from 5 to 8, preferably a pH of from 5.5 to 7.5.

The compositions of the invention are well suited for cosmetic orpharmaceutical use, particularly dermatological use.

The subject compositions are typically formulated for topicalapplication/administration.

In order to further illustrate the present invention and the advantagesthereof, the following specific examples are given, it being understoodthat same are intended only as illustrative and in nowise limitative.

EXAMPLE 1

The capacity of cinnamic acid to promote desquamation of the skin wasexamined:

This test of in vitro screening of an active agent on desquamation wascarried out on differentiated human keratinocytes. The principle of thetest was based on the fact that desquamation induces the release ofcorneocytes. The desquamating power of the product tested will beproportionately greater the larger the number of corneocytes released.

The test procedure was as follows: starting with human skin biopsies,the keratinocytes obtained by separation of the epidermis weredissociated by enzymatic action with trypsin and were cultured at aconcentration of 2×10⁵ cells/ml. Growth and differentiation of thekeratinocytes were obtained by culturing for 10 to 20 days in a specificmedium. Next, after removing the culture medium, the activity of thetest product was evaluated. To do this, two samples were taken at T0 andT60, i.e., just before adding the product and 60 minutes after thisaddition. The samples thus taken were analyzed with a flow cytometer inorder to count the corneocyte population. The flow cytometer made itpossible to distinguish the corneocyte and keratinocyte populations bytreatment with acridine orange, which is specific for cellular DNA. Thisstaining was specific for the keratinocytes since normal corneocytes donot contain a nucleus and thus no DNA.

The cellular detachment index was determined by the difference betweenT60 and T0. The same measurement was carried out for a controlcontaining no test product, since the experimental conditions inevitablyinduced the release of corneocytes, even in the absence of activeagents.

The test was carried out with cinnamic acid at a concentration of5×10⁻⁵M.

The results of these studies are reported in the Table below:

TABLE Compounds at 5 × 10⁻⁵M % p** Reference* 96.6 <0.05 Cinnamic acid59.2 >0.05 Control 0 — *Reference: 2-hydroxy-5-octanoylbenzoic acid,which is known to promote desquamation (FR-85/06953 assigned to theassignee hereof). **:p: confidence interval calculated according to theDunett method.

The results are given as a % of activity relative to the controlconsisting of an identical culture in the absence of compound.

The activity of the cinnamic acid on the cellular detachment, thus, washigh.

EXAMPLE 2

Examples of specific formulations according to the invention; thesecompositions were formulated by simple intimate admixing of the variouscomponents:

Composition 1: Facial milk Liquid petroleum jelly 7.0 g Cinnamic acid2.0 g Glyceryl monostearate, polyethylene glycol stearate 3.0 g (100 EO)Carboxyvinyl polymer 0.4 g Stearyl alcohol 0.7 g Soybean proteins 3.0 gNaOH 0.4 g Preservative qs Water qs 100 g

This composition was in the form of a facial milk having good cosmeticproperties and was mild and comfortable to use.

The pH of the composition was about 5.5.

Composition 2: Lotion Cinnamic acid  0.5 g 2-Ethylhexyl palmitate 10.0 gCyclopentadimethylsiloxane 20.0 g Butylene glycol  5.0 g Preservative qsWater qs 100 g

This lotion, which contained no surfactant, promoted desquamation of theskin.

Composition 3: Milk Octyl palmitate 35.0 g Glycerol  2.0 g Cinnamic acid 2.0 g C10-C30 acrylates/alkylacrylates  0.1 g crosslinked polymerTriethanolamine  0.1 g Amino acids from wheat  1.0 g Preservative qsWater qs 100 g

The milk obtained, which contained no surfactant, had good cosmeticproperties.

Composition 4: Facial gel Glycerol 10.0 g Cinnamic acid  1.0 g Disodiumcocoamphodiacetate  1.0 g Preservative qs Water qs 100 g

The gel obtained had good cosmetic properties.

Composition 5: Cleansing gel with water Butylene glycol 7.0 g Sodiumlauroyl sarcosinate 4.0 g Cinnamic acid 0.5 g Triethanolamine 0.8 gCarbomer 0.5 g Preservatives qs Water qs 100 g

The gel obtained had good cosmetic properties.

While the invention has been described in terms of various preferredembodiments, the skilled artisan will appreciate that variousmodifications, substitutions, omissions, and changes may be made withoutdeparting from the spirit thereof. Accordingly, it is intended that thescope of the present invention be limited solely by the scope of thefollowing claims, including equivalents thereof.

1. A method for promoting desquamation or stimulating epidermal renewal of the skin of a human subject in need of such treatment, comprising topically applying thereto a cosmetic or dermatological composition comprising a desquamation-effective or epidermal renewal-effective amount of an ester of the compound cinnamic acid, said compound cinnamic acid having the formula

said ester of said compound cinnamic acid being formulated into a topically applicable, cosmetically or dermatologically acceptable vehicle, diluent or carrier therefor, said ester of said compound cinnamic being the sole active agent for promoting desquamation or stimulating epidermal renewal in said composition.
 2. A method for promoting desquamation of the skin of a human subject in need of such treatment, comprising topically applying thereto a cosmetic or dermatological composition comprising a desquamation-effective amount of an ester of the compound cinnamic acid, said compound cinnamic acid having the formula

said ester of said compound cinnamic acid being formulated into a topically applicable, cosmetically or dermatologically acceptable vehicle, diluent or carrier therefor, said ester of said compound cinnamic acid being the sole active agent for promoting desquamation in said composition.
 3. A method for stimulating renewal of the epidermal skin of a human subject in need of such treatment, comprising topically applying thereto a cosmetic or dermatological composition comprising an epidermal renewal-effective amount of an ester of the compound cinnamic acid, said compound cinnamic acid having the formula

said ester of said compound cinnamic acid being formulated into a topically applicable, cosmetically or dermatologically acceptable vehicle, diluent or carrier therefor, said ester of said compound cinnamic acid being the sole active agent for stimulating epidermal renewal in said composition.
 4. The method as defined by claim 1, wherein said composition includes only ingredients or amounts thereof which do not cause the side-effect sensations of stinging, tautness, overheating or redness of the skin.
 5. The method defined by claim 2, wherein said composition includes only ingredients or amounts thereof which do not cause the side-effect sensations of stinging, tautness, overheating or redness of the skin.
 6. The method as defined by claim 3, wherein said composition includes only ingredients or amounts thereof which do not cause the side-effect sensations of stinging, tautness, overheating or redness of the skin.
 7. The method as defined by claim 1, wherein the amount of said ester of said compound cinnamic acid ester present in the composition ranges from 10⁻³% to 10% by weight of the total weight.
 8. The method as defined by claim 2, wherein the amount of said ester of said compound cinnamic acid present in the composition ranges from 10⁻³% to 10% by weight of the total weight.
 9. The method as defined by claim 3, wherein the amount of said ester of said compound cinnamic acid present in the composition ranges from 10⁻³% to 10% by weight of the total weight.
 10. The method as defined by claim 7, wherein the amount of said ester of said compound cinnamic acid present in the composition ranges from 10⁻³% to 5% by weight of the total weight.
 11. The method as defined by claim 8, wherein the amount of said ester of said compound cinnamic acid present in the composition ranges from 10⁻³% to 5% by weight of the total weight.
 12. The method as defined by claim 9, wherein the amount of said ester of said compound cinnamic acid present in the composition ranges from 10⁻³% to 5% by weight of the total weight.
 13. The method as defined by claim 1, wherein said composition has a pH ranging from 5 to
 8. 14. The method as defined by claim 2, wherein said composition has a pH ranging from 5 to
 8. 15. The method as defined by claim 3, wherein said composition has a pH ranging from 5 to
 8. 